Greater than 10% of humans suffer chronic sleep disorders, but the genetic mechanisms that regulate sleep are largely unknown. The identification of defective Hypocretin/Orexin (Hcrt) signaling as a cause of narcolepsy provided a genetic entry point into sleep research, but an effective treatment for this disorder has not yet been found. Moreover, only a small fraction of sleep disorders are associated with narcolepsy, indicating that additional genes that control sleep and wakefulness remain to be identified. The objective of this proposal is to use zebrafish as a simple and cost-effective vertebrate model system to study the genetics of Hcrt signaling and sleep. Zebrafish are an excellent model for these studies because they are amenable to high-throughput genetic screens and,unlike invertebrates, have a Hcrt ortholog and the basic brain structures that regulate sleep in mammals. We have shown that Hcrt overexpression causes an insomnia-like phenotype in zebrafish larvae. In Specific Aim 1, we will use pharmacological agents and genetic mutants to determine the genetic and neurologic mechanisms by which Hcrt overexpression induces this phenotype. These experiments will improve understanding of Hcrt function and may provide clues to the basis of chronic insomnia. In Specific Aim 2, we will use zebrafish larvae to perform a high-throughput genetic screen to identify novel sleep regulators. This screen is targeted to classes of genes that are likely to be involved in sleep and provide good drug targets to treat sleep disorders. My immediate career goal is to complete my postdoctoral studies within 2 years and to start my own lab as an independent investigator at a top university or research institute. My long-term career goal is to elucidate the genetic and neurologic mechanisms that regulate sleep/wake states, with the hope that this knowledge will lead to treatments for sleep disorders. In addition to my mentor, I have assembled a team of expert consultants who will aid in my training to help me become a successful independent investigator. Relevance: Over 10% of humans suffer from sleep disorders, yet little is known about the causes of sleep disorders or how sleep is regulated. This proposal will use zebrafish as a model system to study how sleep is regulated by studying a gene whose loss causes the human sleep disorder narcolepsy. Zebrafish will also be used to identify new genes that regulate sleep and may be involved in human sleep disorders.